Novel Role of RanBP9 in BACE1 Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation

Madepalli K Lakshmana,Il-Sang Yoon,Eunice Chen,Elizabetta Bianchi,Edward H Koo,David E Kang

doi:10.1074/jbc.m807345200

Abstract

Accumulation of the amyloid beta (Abeta) peptide derived from the proteolytic processing of amyloid precursor protein (APP) is the defining pathological hallmark of Alzheimer disease. We previously demonstrated that the C-terminal 37 amino acids of lipoprotein receptor-related protein (LRP) robustly promoted Abeta generation independent of FE65 and specifically interacted with Ran-binding protein 9 (RanBP9). In this study we found that RanBP9 strongly increased BACE1 cleavage of APP and Abeta generation. This pro-amyloidogenic activity of RanBP9 did not depend on the KPI domain or the Swedish APP mutation. In cells expressing wild type APP, RanBP9 reduced cell surface APP and accelerated APP internalization, consistent with enhanced beta-secretase processing in the endocytic pathway. The N-terminal half of RanBP9 containing SPRY-LisH domains not only interacted with LRP but also with APP and BACE1. Overexpression of RanBP9 resulted in the enhancement of APP interactions with LRP and BACE1 and increased lipid raft association of APP. Importantly, knockdown of endogenous RanBP9 significantly reduced Abeta generation in Chinese hamster ovary cells and in primary neurons, demonstrating its physiological role in BACE1 cleavage of APP. These findings not only implicate RanBP9 as a novel and potent regulator of APP processing but also as a potential therapeutic target for Alzheimer disease.

Highlights

The major defining pathological hallmark of Alzheimer disease (AD)2 is the accumulation of amyloid ␤ protein (A␤), a neurotoxic peptide derived from ␤- and ␥-secretase cleavages of the amyloid precursor protein (APP)
These data indicate that the C37 region of lipoprotein receptor-related protein (LRP) functions to stabilize the interaction between Ran-binding protein 9 (RanBP9) and APP and suggest that LRP soluble tail (LRP-ST) and/or soluble LRP-C37 acts on APP trafficking and processing possibly by recruiting RanBP9 to APP-containing complexes
The proteolytic processing of APP to generate A␤ is a primary event in the pathogenesis of AD

Summary

Introduction

The major defining pathological hallmark of Alzheimer disease (AD) is the accumulation of amyloid ␤ protein (A␤), a neurotoxic peptide derived from ␤- and ␥-secretase cleavages of the amyloid precursor protein (APP). The LRP soluble tail (LRP-ST) lacking the transmembrane domain and only containing the cytoplasmic tail of LRP is sufficient to enhance A␤ secretion [5] This activity of LRP-ST is achieved by promoting APP/BACE1 interaction [6], the precise mechanism is unknown. RanBP9, known as RanBPM, acts as a multi-modular scaffolding protein, bridging interactions between the cytoplasmic domains of a variety of membrane receptors and intracellular signaling targets. These include Axl and Sky [8], MET receptor protein-tyrosine kinase [9], and ␤2-integrin LFA-1 [10]. We show that RanBP9 robustly promotes BACE1 processing of APP and A␤ generation

Methods

Results

Conclusion